1. Field of the Invention
The present invention relates generally to the fields of biochemistry, molecular biology, and diagnosis and therapy for hyperproliferative cell diseases and conditions, such as cancer and atherosclerosis. More particularly, it concerns a Fortilin polypeptide, the gene or transcript encoding it, modulators of Fortilin and their relevance to cancer and vascular diseases.
2. Description of Related Art
Heart disease and cancer are the leading causes of death, respectively, in the United States. In 1997, 41.2 percent of deaths in the United States (953,110 lives) were caused by a cardiovascular disease, and cancer caused 539,377 deaths (americanheart.org). More than a million Americans are expected to have a heart attack a year, while cancer strikes one in two men and one in three women (Landis, 1998).
The growth of normal cells is a controlled process. A cell whose growth is not controlled may proliferate more frequently, becoming hyperproliferative. Cancer is an example of a disease characterized by hyperproliferative cells. The development of cancer is understood as the culmination of complex, multistep biological processes, occurring through the accumulation of genetic alterations. Many if not all of these alterations involve specific cellular growth-controlling genes that are mutated. These genes typically fall into two categories: proto-oncogenes and tumor suppressor genes. Mutations in genes of both classes generally confer a growth advantage on the cell containing the altered genetic material.
The function of tumor suppressor genes, as opposed to proto-oncogenes, is to antagonize cellular proliferation. When a tumor suppressor gene is inactivated, for example by point mutation or deletion, the cell's regulatory machinery for controlling growth is upset. Tumor suppressor genes include Rb, p53, APC, WT-1, p16, NF-1, NF-2, and VHL.
High levels of mutant p53 have been found in many cells transformed by chemical carcinogenesis, ultraviolet radiation, and several viruses. The p53 gene is a frequent target of mutational inactivation in a wide variety of human tumors and is already documented to be the most frequently mutated gene in common human cancers. It is mutated in over 50% of human NSCLC (Hollstein et al., 1991) and in a wide spectrum of other tumors. The loss of proper p53 functioning is associated with the loss of cell growth control. The lack of proper p53 function can be either due to mutated (or altered) p53 or due to the presence of p53 inhibitors. In recent years, several p53 inhibitors have been identified. These include Mdm-2, Bcl-2, BRCA2, and others. These inhibitors negatively regulate p53 through various mechanisms: Mdm-2 and BRCA2 directly bind to p53, thereby interfering with its function. Bcl-2, on the other hand, blocks the entry of p53 to the nucleus.
p53 has been shown by several laboratories to promote apoptosis, which is programmed cell death. Other proteins, however, have been shown to prevent apoptosis; for example, overexpression of Bcl-xL and MCL1 (Myeloid Cell Leukemia 1), a Bcl-2 homologue, prevented HeLa cells from undergoing apoptosis, consistent with previous reports (Schmitt et al., 1998; Zhou et al., 1997). Cancer alters the regulation of apoptosis, so polypeptides involved in the process of apoptosis have also been implicated in cancer.
The gene products of proto-oncogenes, as alluded to above, typically are involved in pathways of normal cell growth or differentiation. Many of the participants of these pathways, when genetically mutated, contribute to the promotion of tumor development and the genes encoding them are consequently termed “oncogenes.” The polypeptides encoded by proto-oncogenes include transcriptions factors (e.g. c-fos, c-jun, c-myc), growth factor receptors (eg., c-fms, c-erbB, c-kit), growth factors (e.g., c-sis, int-2) and cell cycle proteins (e.g., PRAD1). Mutations in one or more proto-oncogenes—that is, the presence of one or more oncogenes—has been shown to be associated with specific cancers. Unlike tumor suppressors genes involved in cancer, oncogenes express a protein product that possesses activity. Thus, the treatment of cancer may involve inactivating, inhibiting, or reducing the activity of one or more oncogene products.
Currently, there are few effective options for the treatment of many common cancer types. The course of treatment for a given individual depends on the diagnosis, the stage to which the disease has developed and factors such as age, sex and general health of the patient. The most conventional options of cancer treatment are surgery, radiation therapy and chemotherapy. These therapies each are accompanied with varying side effects and they have varying degrees of efficacy. Furthermore, gene therapy is an emerging field in biomedical research with a focus on the treatment of disease by the introduction of therapeutic recombinant nucleic acids into somatic cells of patients. Various clinical trials using gene therapies have been initiated and include the treatment of various cancers, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular disease, Gaucher's disease, rheumatoid arthritis, and others. However, there is a continued need for effective cancer therapies. Moreover, there is a persistent need for diagnostic assays that identify individuals who are predisposed to cancer, as well as to identify the prognosis of a particular cancer patient.
Similarly, there is a need for effective therapies in the treatment of other hyperproliferative cell diseases and conditions, particularly atherosclerosis. Numerous treatments exist for atherosclerosis. However, given the number of patients afflicted with these diseases and conditions involving atherosclerosis, as well as the number who die from diseases involving it, continued efforts to improve therapy are necessary.
As additional therapies and diagnostic methods for hyperproliferative diseases and conditions, such as cancer and atherosclerosis, are needed, the present invention focuses on the interactions discovered between the tumor suppressor p53 and Fortilin and between myeloid cell leukemia (MCLI) and Fortilin, as well as on the anti-apoptotic properties of Fortilin. The present invention concerns compositions and methods involving the Fortilin polypeptide and modulators of Fortilin to address the need for additional therapies and diagnostic methods.